The objectives of the proposed research are to understand the primary action of narcotic analgesic drugs upon single neurons and the way in which these actions alter during the development of physical dependence. The role of enkephalin, endogenous ligands for the opiate receptors, will also be investigated. There is abundant evidence that the myenteric plexus of the guinea-pig ileum contains morphine receptors which are pharmacologically identical to those in brain. The mechanism of action of narcotics is likely to be the same at the two sites. The myenteric plexus will be used as a model system in which to test and expand the hypothesis that the primary receptor-mediated action of narcotics is to stabilize excitable membranes. The nature and mechanism of this effect will be studied by intracellular and extracellular recording techniques. Tissues will be used from both naive and dependent animals, and dependence will be simulated in vitro by incubation of tissue with narcotic agonists. Narcotic agonists and antagonists will be applied by perfusion and by close iontophoresis. The mechanism of action of narcotics on single cells will be studied by manipulating the ionic environment, by inhibiting active ion transport, by interfering with cyclic AMP metabolism and by studying the time course of desensitization. The acute effects of enkephalin will be determined in tissue from naive and dependent animals and its functional role in the myenteric plexus will be assessed. The results obtained are expected to elucidate the way in which enkephalin and narcotic analgesics act upon single neurons in naive and dependent animals, and to assist in the design of non-addictive analgesics. The experiments will also help to differentiate between the primary and secondary changes which occur in single neurons during the development of tolerance and physical dependence.